Overexpression of human LCAT in NZW rabbits (hL-Tg) increased HDL-C, decreased LDL-C and decreased atherosclerosis. Human apoA-I transgenic rabbits (hAI-Tg) have increased HDL-C and decreased atherosclerosis. To study the effect of LCAT and apoA-I coexpression on HDL and LDL metabolism as well as atherosclerosis we crossed low expressor hL-Tg with hAI-Tg rabbits (hL/hAI-Tg).Baseline LCAT act (nm/ml/h) and lipids (mg/dl) in hL/hAI-Tg were:LCAT act=620?15, TC=109?24, TG=61?9, CE=83?23, HDL-C=84?18,and apoA-I=123?13. In hL/AI-Tg, LCAT act,TC,CE,HDL-C and apoA-I were increased (5X,2x,2X,2X & 1.5X, resp; p<0.05 all) vs NZW controls (C) and increased(1X,3X,4X & 2X,resp; p<0.05) compared to L-Tg. FPLC analysis revealed large, CE-rich HDL in hL/hAI-Tg. 125I-apoA-I,131I-LDL and 3H-CE-HDL were injected into hL- Tg(n=4),hL/hAI-Tg(n=4) and C(n=5) rabbits. The FCR of apoA-I in the hL/hAI-Tg(0.447?0.080d-1) was decreased (p<0.05;both) vs C (1.032?0.141d-1 )and hL-Tg(0.758?0.030d-1) and the production rate (PR) of apoA-I in hL/hAI-Tg(21.35?2.79mg/kg.d) was increased (p<0.05;both) vs C(14.04?1.92 mg/kg.d) and hL-Tg(15.90?0.63mg/kg.d).3H-CE HDL clearance (FCR) in the hL/hAI-Tg(1.85? 0.25d-1) was decreased (p<0.05) vs C(5.94?0.74d-1) and hL-Tg (4.99?0.50d-1). In contrast, the catabolism of 131I-LDL in hL/AI-Tg(9.36?1.38d-1) and hL-Tg(5.63?0.26d- 1) was increased vs C(4.50?0.59d-1; p<0.05). In summary:1)Coexpression of hLCAT and hApoA-I in Tg-rabbits increased TC,CE,HDL-C and apoA-I and leads to the accumulation of large, CE-rich HDL. 2)The increased apoA-I and HDL-C is due to increased synthesis/delayed catabolism of apoA-I as well as decreased clearance of HDL-CE. 4)LDL catabolism is markedly increased in hL/hAI-Tg. 5)ApoA-I expression further increases HDL-C and LDL clearance in hL-Tg rabbits resulting in a more protective lipoprotein profile. 6)Combined LCAT/apoA-I expression may represent an ideal anti-atherogenic treatment strategy.